Process for the preparation of aclidinium bromide

Abstract

A process for preparing (3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) comprises reacting 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R) yl methyl ester and 3-phenoxypropyl bromide, wherein the reaction takes place in a solvent or mixture of solvents selected from the group of amides and/or the group of solvents with a sulfoxide group. Also provided is a crystalline aclidinium bromide characterized by a powder XRPD pattern having peaks at 7.7±0.2° 2θ, 10.4±0.2° 2θ, 13.2±0.2° 2θ, 13.8±0.2° 2θ, 19.9±0.2° 2θ, 20.3±0.2° 2θ, 20.8±0.2° 2θ, 24.2±0.2° 2θ, 25.7±0.2° 2θ, 26.1±0.2° 2θ, 29.2±0.2° 2θ, 30.8±0.2° 2θ. A pharmaceutical composition comprises aclidinium bromide according to the invention and a pharmaceutically acceptable excipient.

The invention claimed is: 
     
       1. A process for preparing (3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) by reacting 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R) yl methyl ester and 3-phenoxypropyl bromide, wherein the reaction takes place in a solvent or mixture of solvents selected from the group of amides and/or the group of solvents with a sulfoxide group. 
     
     
       2. The process according to  claim 1  wherein the reaction temperature is below 100° C. 
     
     
       3. The process according to  claim 1  wherein the reaction temperature is from about 30° C. to about 20° C. 
     
     
       4. The process according to  claim 1  wherein the reaction temperature is about 20° C. 
     
     
       5. The process according to  claim 1  wherein the reaction takes place under a flow of an insert gas. 
     
     
       6. The process according to  claim 1  wherein the reaction takes place at a pressure below the atmospheric pressure. 
     
     
       7. The process according to  claim 1  wherein the alcohol formed is removed from the reaction mixture. 
     
     
       8. The process according to  claim 1  wherein the solvent is DMF or is a mixture of solvents containing DMF. 
     
     
       9. The process according to  claim 1  wherein the solvent is DMA or is a mixture of solvents containing DMA. 
     
     
       10. The process according to  claim 1  wherein the solvent is DMSO or is a mixture of solvents containing DMSO. 
     
     
       11. The process according to  claim 1  wherein the equivalent mole ratio of 3-phenoxypropyl bromide to 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R) yl methyl ester is in the range of from 1.2 to 2.0. 
     
     
       12. The process according  claim 11  wherein the range is from 1.5 to 2.0. 
     
     
       13. The process according to  claim 1  wherein the reaction time is not more than 8 hours. 
     
     
       14. The process according to  claim 13  wherein the reaction time is not more than 6 hours. 
     
     
       15. The process according to  claim 1  further comprising the step of purification of aclinidium bromide by dissolving the product in DMSO and using acetonitrile as co-solvent to precipitate the purified product. 
     
     
       16. The process according to  claim 1  wherein the aclidinium bromide obtained is crystalline. 
     
     
       17. The process according to  claim 16  wherein the aclidinium bromide is characterized by a powder XRPD pattern having peaks at 7.7±0.2° 2θ, 10.4±0.2° 2θ, 13.2±0.2° 2θ, 13.8±0.2° 2θ, 19.9±0.2° 2θ, 20.3±0.2° 2θ, 20.8±0.2° 2θ, 24.2±0.2° 2θ, 25.7±0.2° 2θ, 26.1±0.2° 2θ, 29.2±0.2° 2θ, 30.8±0.2° 2θ. 
     
     
       18. The process according to  claim 17 , wherein the aclidinium bromide is further characterized by no weight loss by TGA. 
     
     
       19. The process according to  claim 17 , wherein the aclidinium bromide is further characterized by a DSC thermogram having an endotherm peak at 228° C. 
     
     
       20. The process according to  claim 1  where the aclidinium bromide obtained is a mixture of crystalline and amorphous material. 
     
     
       21. The process according to  claim 20  where the mixture of crystalline and amorphous aclidinium bromide is characterized by a powder XRPD pattern as depicted in  FIG. 9 . 
     
     
       22. The process according to  claim 20  wherein 20 wt % or less, as a percentage of the total weight of material, of amorphous aclidinium bromide is present. 
     
     
       23. The process according to  claim 1  further comprising drying a solution comprising aclidinium bromide in a solvent or a mixture of solvents. 
     
     
       24. The process according to  claim 23  wherein the said solvent or mixture of solvents are selected from the group of solvents with a sulfoxide group. 
     
     
       25. The process according to  claim 23  wherein the said mixture of solvents contain at least one solvent selected from the group of solvents with a sulfoxide group. 
     
     
       26. The process according to  claim 23  wherein the said mixture of solvents contain DMSO. 
     
     
       27. The process according to  claim 23  wherein the said solvent is DMSO. 
     
     
       28. The process according to  claim 1  wherein the reaction temperature is below 50° C. 
     
     
       29. The process according to  claim 1  wherein the reaction temperature is about 30° C. 
     
     
       30. The process according to  claim 1  wherein the reaction takes place under a flow of a dry inert gas. 
     
     
       31. The process according to  claim 1  wherein the reaction takes place under a flow of dry nitrogen, dry helium or a mixture thereof. 
     
     
       32. The process according  claim 11  wherein the equivalent mole ratio of 3-phenoxypropyl bromide to 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R) yl methyl ester is 1.8. 
     
     
       33. The process according to  claim 13  wherein the reaction time is not more than 4 hours. 
     
     
       34. The process according to  claim 20  wherein 10 wt % or less, as a percentage of the total weight of material, of amorphous aclidinium bromide is present. 
     
     
       35. The process according to  claim 1  further comprising drying a solution of aclidinium bromide in a solvent or a mixture of solvents by spray drying.